Structural and Mechanistic Elucidation of NAIP/NLRC4 Inflammasomes in Innate Immunity

先天免疫中 NAIP/NLRC4 炎症小体的结构和机制阐明

• 批准号: 10065718
• 负责人: Liman Zhang
• 金额: $ 24.46万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065718
• 关键词: 3-Dimensional; Achievement; Address; Award; BIR Domain; Bacteria; Bacterial Infections; Biochemical; CASP1 gene; Caspase; Cell Death; Cells; Cellular biology; Colitis associated colorectal cancer; Complex; Cryoelectron Microscopy; Data; Development; Development Plans; Diabetes Mellitus; Disease; Educational workshop; Environment; Family; Flagellin; Gingivitis; Goals; Gout; Gram-Negative Bacteria; Host Defense; Human; Immune response; Immune system; Immunologist; Immunology; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-1 beta; Interleukin-18; International; Knowledge; Lead; Learning; Legionella pneumophila; Legionnaires' Disease; Ligands; Link; Macrophage activation syndrome; Malignant Neoplasms; Mediating; Medical center; Mentors; Mentorship; Metabolic Diseases; Modeling; Molecular; Molecular Conformation; Molecular Medicine; Mus; Mutation; Mutation Analysis; N-terminal; Natural Immunity; Needles; Non-Insulin-Dependent Diabetes Mellitus; Parkinson Disease; Pathogenicity; Pattern; Periodontitis; Play; Process; Production; Proteins; Pseudomonas; Psoriasis; Publishing; Regulation; Research; Rod; Role; Sagittaria; Salmonella; Salmonella typhimurium; Science; Series; Signal Transduction; Specificity; Structure; System; Techniques; Testing; Training; Training Programs; Type III Secretion System Pathway; Work; autoinflammation; base; career; career development; conformational conversion; cytokine; dalton; drug development; insight; medical schools; mouse model; nanoscale; novel therapeutic intervention; novel therapeutics; pathogen; polymerization; programs; protein complex; receptor; reconstitution; reconstruction; recruit; screening; small molecule; small molecule inhibitor; structural biology; symposium; therapy development; tumorigenesis

Background: The NAIP/NLRC4 inflammasomes are defenders against cytosolic infections by bacteria such as Salmonella and Pseudomonas through recruitment and activation of pro-caspase-1, lead to the production of interleukin-1β (pro-IL-1β) and IL-18, and induces pyroptotic cell death. The NAIP/NLRC4 inflammasomes are comprised with three components, the bacterial ligands such as flagellin, the NAIPs, and the NLRC4 protein. NAIPs recognize different bacterial ligands and determine the specificity of NAIP/NLRC4 inflammasomes. Abnormal inhibition and activation of these complexes cause human inflammatory diseases, NLRC4 mutation also related with the colitis-associated colorectal cancer (CAC). This project on structural and biochemical studies of the NAIP/NLRC4 inflammasomes will provide important insights into cytosolic bacteria sensing mechanisms and lead to new strategies on disease treatment and drug development. Research/Career Goals: My short-term goal is to understand the structural basis of how NAIP/NLRC4 inflammasome are activated by bacterial ligand, and the long-term goal is to understand the complicated immune responses upon pathogen infection. The specific aims of this project are to elucidate the mechanism of ligand recognition by NAIP and NLRC4, the autoinhibited conformation of NAIP, and to identify small molecule inhibitors of CARD-CARD interactions in inflammasomes. Research/Career Development Plan and Environment: I will take cryo-EM workshops at Harvard Medical School (HMS) and Center for Nanoscale Systems (CNS), learn cell biology and small molecule screening techniques from the mentor's lab, and complete the proposed study. I will attend a series of international conferences to expand my knowledge in immunology. Under the mentorships of Drs. Hao Wu (BCH), Maofu Liao (HMS) and Timothy J. Mitchison (HMS), I will follow the traditional training program to maximize my professional abilities for transition into independence. Program in Cellular and Molecular Medicine (PCMM) at BCH and HMS will provide me with the great environment for scientific achievement and career development to become an independent structural immunologist during this award.

背景：NAIP/NLRC 4炎性小体是抵抗细菌胞浆感染的防御者， 沙门氏菌和假单胞菌通过募集和激活caspase-1原，导致 白细胞介素-1 β（pro-IL-1β）和IL-18，并诱导热凋亡细胞死亡。NAIP/NLRC 4炎性小体是 包括三种组分，细菌配体如鞭毛蛋白、NAIP和NLRC 4蛋白。 NAIP识别不同的细菌配体并确定NAIP/NLRC 4炎性小体的特异性。 这些复合物的异常抑制和激活导致人类炎症性疾病，NLRC 4突变 与结肠炎相关的结直肠癌（CAC）也有相关性。这个关于结构和生物化学的项目 NAIP/NLRC 4炎性小体的研究将为胞质细菌传感提供重要的见解 机制，并导致疾病治疗和药物开发的新策略。 研究/职业目标：我的短期目标是了解NAIP/NLRC的结构基础4 炎症小体被细菌配体激活，长期目标是了解复杂的 病原体感染后的免疫反应。本项目的具体目标是阐明 通过NAIP和NLRC 4的配体识别，NAIP的自抑制构象，并识别小的 炎性小体中CARD-CARD相互作用的分子抑制剂。 研究/职业发展计划和环境：我将参加哈佛医学院的冷冻EM研讨会 学校（HMS）和纳米系统中心（CNS），学习细胞生物学和小分子筛选 技术从导师的实验室，并完成拟议的研究。我将参加一系列国际 参加一些会议来拓展我的免疫学知识在吴昊博士（BCH）、毛福 Liao（HMS）和Timothy J. Mitchison（HMS），我将遵循传统的培训计划，以最大限度地提高我的 具备向独立过渡的专业能力。细胞与分子医学（PCMM） BCH和HMS将为我的科学成就和职业发展提供良好的环境 成为一名独立的结构免疫学家。